Humans and other primates have the remarkable ability to adjust behaviors according to internally stored goals and contexts. This flexibility permits complex cognition and is known to depend upon the functions of the prefrontal cortex (PFC). Accordingly, dysfunction of the PFC impairs flexibility of action leading to impulsive, perseverative, and disorganized behaviors. Such cognitive deficits are evident in patients with neurological damage (e.g. traumatic-brain injury, stroke), as well as in patients with psychiatric disorders (e.g. schizophrenia, attention-deficit hyperactivity disorder). Commensurately, there has been a great deal of interest in explicating organizing principles to describe PFC function. Two such principles are: 1) that the PFC is organized along a rostral-caudal axis with more rostral areas providing hierarchical top-down control over more caudal areas; 2) that the PFC is organized along a dorsal-ventral axis of content with more dorsal areas maintaining spatial information and more ventral areas maintaining identity or object information. What remains unclear is how these two axes interact to achieve flexible cognitive control. The present proposal seeks to fill this gap by coupling working memory tasks that are known to engage dissociable dorsal-ventral networks in the caudal PFC with cognitive control demands that are known to engage dissociable rostral-caudal areas. The proposal will test the hypothesis that the dorsal-ventral axis converges in rostral areas of the PFC allowing rostral areas of the PFC (areas 10 & 46) to exert domain-general control over domain-specific caudal areas of the PFC (areas 6/8 & 44). This hypothesis is drawn from documented patterns of anatomical connectivity. The PFC will be explored through a combination of fMRI, transcranial magnetic stimulation (TMS), and studies of patients with focal PFC lesions. The combination of approaches affords the ability to document the organization of the PFC through patterns of neural activation and test causal functional roles of particular PFC regions through the effect of circumscribed lesions. Given the centrality of the PFC in cognitive control, it is anticipated that elucidating the interaction between the rostral-caudal and dorsal-ventral axes of the PFC will provide critical insight into complex behaviors that require high levels of mental organization. PUBLIC HEALTH RELEVANCE: Dysfunctions of the prefrontal cortex (PFC) have a deleterious impact on cognitive function, which is one of the most critical determinants of quality of life in patients. Furthermore, cognitie and behavioral deficits from PFC damage are particularly challenging to treat. Elucidating the functional organization of the PFC is expected to enhance our understanding of PFC-related cognitive impairments, thereby leading to improved diagnosis and rehabilitation.